1. Introduction.
The following description includes information that may be useful in understanding the present invention. It is not an admission that any such information is prior art, or relevant, to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.
2. Background.
Atherosclerosis is the most common cause of ischemic heart disease. When considered separately, stroke is the third leading cause of death, with the vast majority of strokes being the result of ischemic events. However, arteriosclerosis is a quite common inflammatory response, and atherosclerosis without thrombosis is in general a benign disease. Several studies indicate that the plaque composition rather than the degree of stenosis is the key factor for predicting vulnerability to rupture or thrombosis. Such thrombosis-prone or high-risk plaques are referred to as “vulnerable” plaques.
Plaque rupture is triggered by mechanical events, but plaque vulnerability is due to weakening of the fibrous cap, interplaque hemorrhage, and softening of plaque components, often as a result of infection and macrophage and T-cell infiltration. In general, lipid-rich, soft plaques are more prone to rupture than collagen-rich, hard plaques. Several morphological and physiological features are associated with vulnerable and stable plaque. Morphological characteristics suggest structural weakness or damage (thin or ruptured fibrous cap, calcification, negative remodeling, neovascularization, large lipid deposits, etc.), while physiological features suggest chemical composition, active infection, inflammatory responses, and metabolism. Many of the factors are subjective or qualitative, reflecting the fact that not all characteristics have been validated as risk determinants. The validation of risk factors requires long-term longitudinal clinical studies, endarterectomies, or autopsies.
Several invasive methods have been used to identify vulnerable plaque, including intravenous ultrasound (IVUS), angioscopy, intravascular MR, and thermography. Since invasive methods expose the patient to significant risk of stroke and MI, they are not appropriate for screening or serial examination. Finally, since these methods require the use of a catheter, estimates of overall vascular plaque burden must be extrapolated from examination of only a few local plaque deposits. Moreover, due to physical constraints such as catheter and artery size, arterial branching, etc., much of a patient's vasculature is inaccessible to invasive instruments.
While MRI has been used to identify morphological plaque features, such as plaque size and fibrous cap thickness, with high sensitivity and specificity, most efforts to characterize plaque involve visual inspection of CAT or MRI scans by expert radiologists. This is a time-consuming (and thus expensive) and error-prone process, subject to several subjective biases, not least that humans are notoriously poor at simultaneously assessing statistical relationships between more than two or three variables. A natural tendency is to focus on gross boundaries and local textures. When considering multimodal images, this problem is multiplied several-fold because in order to digest all the available evidence, the analyst has to assess, pixel-by-pixel, the local environment in as many as four distinct modalities. Typically, this forces the analyst to concentrate on only one modality, with the “best” contrast for a particular tissue, and disregard potential contrary evidence in the other modalities. Classification accuracy is subject to variability between researchers and even for the same researcher over time, making a standardized diagnostic test virtually impossible. In most cases, validation of the interpreted image can only be accomplished by histological examination of endarterectomies.
Given these importance of plaque detection and analysis to patient health, there is a clear need for improved methods for the detection and analysis of plaque in vivo.
3. Definitions.
Before describing the instant invention in detail, several terms used in the context of the present invention will be defined. In addition to these terms, others are defined elsewhere in the specification, as necessary. Unless otherwise expressly defined herein, terms of art used in this specification will have their art-recognized meanings.
A “medical imaging system” refers to any system that can be used to gather, process, and generate images of some or all of the internal regions a patient's body. Typically such systems include a device to generate and gather data, as well as a computer configured to process and analyze data, and frequently generate output images representing the data. Devices used to generate and gather data include those that are non-invasive, e.g., magnetic resonance imaging (“MRI”) machines, positron emission tomography (“PET”) machines, computerized axial tomography (“CAT”) machines, ultrasound machines, etc., as well as devices that generate and collect data invasively, e.g., endoscopes (for transmission of visual images from inside a cavity or lumen in the body) and catheters with a sensing capability. Data collected from such devices are then transmitted to a processor, which in at least some cases, can be used to produce images of one or more internal regions of the patient's body. A healthcare professional trained to interpret the images then examines and interprets the images to generate a diagnosis or prognosis.
A “patentable” composition, process, machine, article of manufacture, or improvement according to the invention means that the subject matter satisfies all statutory requirements for patentability at the time the analysis is performed. For example, with regard to novelty, non-obviousness, or the like, if later investigation reveals that one or more claims encompass one or more embodiments that would negate novelty, non-obviousness, etc., the claim(s), being limited by definition to “patentable” embodiments, specifically exclude the unpatentable embodiment(s). Also, the claims appended hereto are to be interpreted both to provide the broadest reasonable scope, as well as to preserve their validity. Furthermore, if one or more of the statutory requirements for patentability are amended or if the standards change for assessing whether a particular statutory requirement for patentability is satisfied from the time this application is filed or issues as a patent to a time the validity of one or more of the appended claims is questioned, the claims are to be interpreted in a way that (1) preserves their validity and (2) provides the broadest reasonable interpretation under the circumstances.
The term “treatment” or “treating” means any treatment of a disease or disorder, including preventing or protecting against the disease or disorder (that is, causing the clinical symptoms (or the underlying process that may produce or contribute to the symptoms) not to develop); inhibiting the disease or disorder (i.e., arresting or suppressing the development of clinical symptoms, or suppressing progression of one or more underlying process that contributes to the pathology that may produce symptoms); and/or relieving the disease or disorder (i.e., causing the regression of clinical symptoms; or regression of one or more processes that contribute to the symptoms). As will be appreciated, it is not always possible to distinguish between “preventing” and “suppressing” a disease or disorder since the ultimate inductive event or events may be unknown or latent. Accordingly, the term “prophylaxis” will be understood to constitute a type of “treatment” that encompasses either or both “preventing” and/or “suppressing”. The term “protection” thus includes “prophylaxis”.